Journal
CANCER RESEARCH
Volume 75, Issue 7, Pages 1287-1297Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-2444
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Funding
- Spanish grants [SAF2011-22897]
- RTICCs [RD12/0036/0045, RD12/0036/0015]
- Fondo de Investigacion Sanitaria [FIS PI11/929]
- European Community [HEALTH-F2-2010-258677-CURELUNG]
- Associazione ltaliana per la Ricerca sul Cancro [AIRC IG9227, IG13403]
- Spanish MINECO
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Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis. (C)2015 AACR.
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